ISSN 2465-8243(Print) / ISSN: 2465-8510(Online) https://doi.org/10.14777/uti.2017.12.1.22 Review Urogenit Tract Infect 2017;12(1):22-27

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Is Urethral Pain Syndrome Really Part of Bladder Pain Syndrome?

Sung Tae Cho

Department of , Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea

Urethral pain syndrome is a symptom complex that includes , urinary Received: 24 March, 2017 urgency, frequency, nocturia, and persistent or intermittent urethral and/or pelvic Revised: 10 April, 2017 Accepted: 10 April, 2017 pain in the absence of proven . Bladder pain syndrome is a clinical diagnosis, based primarily on chronic symptoms of pain from the bladder and/or pelvis associated with urinary urgency or frequency in the absence of identified cause for the symptoms. To date, the term, urethral pain syndrome, remains to be unclear in referring to a distinct subgroup of bladder pain syndrome. However, these two syndromes share many similarities, except the organ of pain. This review is intended to summarize the current state of literature with regard to similar pathophysiology and possible interrelations between urethral pain syndrome and bladder pain syndrome.

Keywords: Cystitis, interstitial; ; Correspondence to: Sung Tae Cho http://orcid.org/0000-0002-4691-6159 Department of Urology, Hallym University Kangnam Copyright 2017, Korean Association of Urogenital Tract Infection and . All rights reserved. Sacred Heart Hospital, Hallym University College of This is an open access article distributed under the terms of the Creative Commons Attribution Medicine, 1 Singil-ro, Yeongdeungpo-gu, Seoul 07441, Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits Korea unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is Tel: +82-2-829-5198, Fax: +82-2-846-5198 properly cited. E-mail: [email protected]

INTRODUCTION chronic pelvic pain [4]. Urethral pain syndrome and BPS have a lot in common, The term “” was used in 1965 by except the organ of pain. To aid in understanding the Gallagher et al. [1]. In 2002, the term “urethral pain syndrome” possible relationship between these two syndromes, we was implemented by the International Continence Society summarized both syndromes and presented evidence-based (ICS) to delineate the occurrence of recurrent episodic information on whether additional similarities with regard urethral pain, usually on voiding, with daytime frequency to pathophysiology exist between these two syndromes. and nocturia, in the absence of proven infection. It is often common for dyspareunia to also be described. Regardless URETHRAL PAIN SYNDROME of the symptoms, the lack of evidence of or other obvious pathologies is essential [2]. Due Urethral pain syndrome is a symptom complex that to these nonspecific symptoms, there are often overlaps includes dysuria, urinary urgency, frequency, nocturia, and with disease pictures, such as /bladder persistent or intermittent urethral and/or pelvic pain in the pain syndrome (IC/BPS) or the (OAB). absence of proven infection [2]. The diagnosis implies a As such, some authors describe the urethral syndrome as specific duration of symptoms, a minimum of six months an early form of IC [3]. In the current guidelines of the [5]. The exact etiology is unknown; however, infectious European Association of Urology (EAU), urethral pain and psychogenic factors, urethral spasms, early IC, hypoe- syndrome is considered to be a part of the complex of strogenism, squamous metaplasia, as well as gynecological

22 Sung Tae Cho. Urethral Pain Syndrome of BPS 23 risk factors are discussed [6]. There is now evidence that ulcer. For several years, this finding was the hallmark of the microscopic paraurethral glands connected to the distal IC, and urologists would look for ulcers but failed to make third of the urethra in the prevaginal space are homologous the diagnosis in their absence [13]. to the . They stain histologically for prostate-specific The Interstitial Cystitis Association (ICA), established in antigen and, like the prostate, are subject to infection and 1984, succeeded in gaining the National Institute of Diabetes cancer. Some researchers have theorized that inflammation and Digestive and Kidney Diseases (NIDDK)’s interest in of the female prostate (Skene glands and the paraurethral glands) the research for this field [15]. In an effort to define IC, may explain the causes of urethral pain syndrome [7]. the NIDDK held a workshop in August 1987, at which point The diagnosis is mainly based on symptoms. However, in time, the consensus diagnostic criteria were established it is important to rule out other conditions, including for the diagnosis of IC [16]. After the pilot studies to test paraurethral pathology, , atrophic urethral for the criteria, they were revised at the follow-up NIDDK changes, and [5]. The incidence and prevalence workshop in 1988 [15,16]. These criteria were specifically of this condition is not well known thus far due to the designed for the basic and clinical research purposes, but lack of consensus in the method of diagnoses. In several not as a diagnostic tool for the clinician (Table 1) [17]. studies, 15-30% of women who presented with lower urinary tract symptoms (LUTS) were diagnosed with urethral pain PAINFUL BLADDER SYNDROME syndrome [8,9]. Most of these patients are women aged 20 to 30 years and 50 to 60 years. Contrary to the earlier The ICS has been standardizing the terminology of lower definition, urethral pain syndrome may also occur in men, urinary tract diseases. In 2002, for the first time, the ICS but less frequently [6,10]. This condition is more common defined IC, calling it a painful bladder syndrome (PBS), in Caucasians than other races [5]. As a result of these delineating it as: “the complaint of suprapubic pain related nonspecific symptoms, patients with urethral pain syndrome to bladder filling, accompanied by other symptoms, such often enter into urological care after long-term suffering as increased daytime and night-time frequency, in the and repeated treatment [6,11]. absence of proven urinary infection or other obvious pathology [18,19].” The ICS reserves the diagnosis of IC INTERSTITIAL CYSTITIS as a “specific diagnosis that requires confirmation by typical cystoscopic and histological features.” This definition may The first known modern documentation of a condition miss 36% of patients, primarily because it confines the pain resembling IC appeared in the early 19th century. Philip to a suprapubic location and mandates a relationship of Syng Physick described an inflammatory condition of the pain to bladder filling [18]. This disorder, despite confusion, bladder with an “ulcer” producing the same symptoms as came to be known as PBS/IC or IC/PBS. a in 1808 [12]. He expanded this concept to include chronic frequency, urgency, and pain syndrome, BLADDER PAIN SYNDROME occurring in the absence of demonstrable etiology, which was called the ‘tic douloureux of the bladder’ in 1836 [12,13]. The European Society for the Study of Interstitial Cystitis This may represent the first description of IC. Fifty years (ESSIC) proposed a new definition and another name change later, Skene used the term IC to describe an inflammation from IC/PBS to BPS alone. The ESSIC paper, published that had “destroyed the mucous membrane partly or wholly in 2008, proposed the following definition: “Chronic (six and extended to the muscular parietes” in 1887 [14]. months or more) pelvic pain, pressure or discomfort However, because of the distinctive clinical characterization perceived to be related to the urinary bladder accompanied of the syndrome, the physician who is always remembered by at least one other urinary symptom like persistent urge and quoted is Guy Hunner [13]. Early in the 20th century, to void or urinary frequency. Confusable diseases as the he described a symptom complex of bladder pain associated cause of the symptoms must be excluded [20].” with distinguishing cystoscopic feature of mucosal lesions ESSIC also introduced a new classification system of BPS as the “elusive ulcer,” which was later termed Hunner’s types and a list of confusable diseases. BPS is indicated

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Table 1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) revised the criteria for interstitial cystitis in 1988 To be included as IC, patients must have either glomerulations on cystoscopic examination or a classic Hunner’s ulcer, and they must have either pain associated with the bladder or urinary urgency. Examination for glomerulations should occur after distension of the bladder under to 80-100 cmH2O for 1-2 min. The bladder may be distended up to two times before evaluation. The glomerulations must be diffuse–present in at least 3 quadrants of the bladder –and there must be at least 10 glomerulations per quadrant. The glomerulations must not be along the path of the cystoscope (to eliminate artifact from contact instrumentation). The presence of any one of the following will exclude the diagnosis of interstitial cystitis: 1. Bladder capacity of greater than 350 ml on awake cystometry using either a gas or liquid filling medium 2. Absence of an intense urge to void with the bladder filled to 100 ml of gas or 150 ml of water during cystometry, using a fill rate of 30-100 ml/min 3. The demonstration of phasic involuntary bladder contractions on cystometry using the fill rate described above 4. Duration of symptoms less than 9 months 5. Absence of nocturia 6. Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics 7. A frequency of urination while awake of less than eight times per day 8. A diagnosis of bacterial cystitis or within a 3-month period 9. Bladder or lower ureteral calculi 10. Active genital herpes 11. Uterine, cervical, vaginal, or urethral cancer 12. Urethral diverticulum 13. Cyclophosphamide or any type of chemical cystitis 14. Tuberculous cystitis 15. Radiation cystitis 16. Benign or malignant bladder tumors 17. Vaginitis 18. Age less than 18 years Adapted from Bladder pain syndrome (Interstitial Cystitis) and related disorders. In: Campbell-Walsh urology. 10th ed. Philadelphia: Saunders; 2012. p. 334-70 [17]. by two symbols: The first corresponds to with HYPERSENSITIVE BLADDER SYNDROME hydrodistention (CHD) findings (1, 2, or 3, indicating increasing grade of severity), and the second to biopsy Homma [24] proposed that frequency/urgency syndrome findings (A, B, and C, indicating increasing grade of is characterized by frequency (frequent voiding) and urgency pathologic severity) [20]. Although neither CHD nor bladder (strong desire to void). It is an inclusive term that incorporates biopsy was prescribed as an essential part of the evaluation, OAB, hypersensitive bladder syndrome (HBS), and other categorizing patients in terms of whether they have conditions that are associated with frequency and urgency. undergone the procedure with results, made it possible Urgency in OAB is characterized by a sudden onset and/or to follow patients with similar findings and study each fear of leakage, while urgency in HBS is characterized by identified cohort to compare the natural history, prognosis, persistent nature and is associated with the fear of pain. and response to therapy [20]. The definition of ESSIC is OAB-wet is a subgroup of OAB, while PBS is a subgroup a clinically useful one, and changes made since its original of HBS with pain. IC is one of the diseases manifested iteration have likely made it more sensitive and inclusive by frequency/urgency and overlapping with HBS and PBS [21]. [24,25]. The panel of the Society for Urodynamics and Female A clinical guideline and algorism for IC and HBS has Urology (SUFU) produced a slightly different definition for been developed by a group of East Asian (Japan, Korea, IC/BPS in 2008: “An unpleasant sensation (pain, pressure, and Taiwan) urologists as a revised form of the Japanese discomfort), perceived to be related to the urinary bladder, guideline for IC [26]. This East-Asian guideline defines IC associated with LUTS for more than six weeks, in the absence as a disease of the urinary bladder diagnosed by three of infection or other identifiable causes” [22]. The SUFU following conditions: 1) a characteristic complex of LUTS, definition was adopted in the guidelines of the American 2) bladder pathology, such as Hunner’s ulcer and bladder Urological Association (AUA) in 2011, along with the bleeding after overdistention, and 3) exclusions of nomenclature IC/BPS, without differentiating between the confusable diseases. The characteristic symptom complex two [23]. is termed, HBS, which is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without

Urogenit Tract Infect Vol. 12, No. 1, April 2017 Sung Tae Cho. Urethral Pain Syndrome of BPS 25 bladder pain. For the definite diagnosis of IC, cystoscopy introitus in women, and the prostatic ducts and urethra or hydrodistention is crucial; HBS is the diagnosis when in men. Because patients with LUDE may experience pain IC is suspected, but not confirmed by the 3 requirements. in one or more locations throughout the pelvis in any combination, it is important for physicians to avoid making NEW PARADIGM a diagnosis solely based on the site of pain. A useful diagnostic tool is the intravesical potassium sensitivity test, which detects The paradigm change has resulted in altering what was the abnormal epithelial permeability of LUDE [32]. originally considered a bladder disease (IC) to a chronic There is also evidence that the urothelium in the region pain syndrome (BPS). IC/BPS is now viewed not only of the urethra may play a role in continence and sensation. through the paradigm of chronic pain syndrome manifesting It has been suggested that symptoms of pain that arise through bladder-related symptoms, but as a syndrome that from the lower urinary tract might originate principally from may not only isolated to the bladder alone [17]. There may the bladder neck and proximal urethra [33]. The bladder be many causes of chronic pelvic pain. When a cause neck and proximal urethral contain the largest density of cannot be determined, the condition is characterized as bladder nerves, and the epithelial cells that line the surface pelvic pain syndrome. If it can be distinguished as urologic, show neuronal-like properties [34]. Thus urethral epithelial- it is further categorized by the organ system. A urologic neural interactions could lead to a “urethral instability” pain syndrome can sometimes be further differentiated influencing the storage and voiding reflexes, and resulting based on the site of perceived pain. These pain syndromes in symptoms of urgency and pain [34,35]. include bladder, urethra, prostate, testicular, and epididymal pain syndromes. The types of BPS can be further defined CONCLUSIONS as IC or simply categorized by ESSIC criteria [17,22]. Urethral pain syndrome is an occurrence of recurrent URETHRA AND BLADDER episodic urethral pain usually on voiding with frequency PATHOPHYSIOLOGY IN PAIN and nocturia. BPS is chronic pelvic pain, pressure, or SYNDROME discomfort often exacerbated by bladder filling, and associated with urinary frequency. Seemingly, two different IC/BPS is a chronic disease characterized by prolonged syndromes that would usually seem nothing like one another duration of symptoms of pelvic or perineal pain, thinning have much in common when it comes to the new paradigm of the bladder epithelium, and various voiding symptoms, and pathophysiology. such as nocturia, increased urinary frequency, and urgency. Chronic pelvic pain can have multiple causes, including In terms of pain, suprapubic or bladder pain is prominent. many types of urologic pain syndromes. In broad terms, However, many patients report different and/or additional urologic pain syndrome encompasses urethral pain sites, particularly in the urethra, genitalia, and lower back syndrome and BPS. Pain arising from the lower urinary [27,28]. Although the cause of BPS is usually unknown, tract may originate from the bladder neck and proximal there is a body of evidence supporting the involvement urethra, and LUDE can affect tissues of the bladder and of bladder urothelial abnormalities in these illnesses [29,30]. urethra. Even if controversies still remain, urethral pain Parsons showed that a leaky dysfunctional epithelium and syndrome can be a part of BPS. Further basic science and subsequent diffusion of potassium into the tissue may be clinical research in this area is needed to better understand responsible for the pelvic pain [10]. These altered the the pathophysiology of these syndromes. paradigms in the generation of frequency, urgency, and pelvic pain. After all, urethral pain syndrome and BPS have CONFLICT OF INTEREST all been shown to have epithelial leak and potassium sensitivity, uniting these syndromes into one disease, lower No potential conflict of interest relevant to this article urinary tract dysfunction epithelium (LUDE) [10,31]. was reported. LUDE can affect the bladder, urethra, labia or vaginal

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